Cyanokit

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Cyanokit

CLINICAL PHARMACOLOGY

Mechanism of Action

Cyanide is an extremely toxic poison. In the absence of rapid and adequate
treatment, exposure to a high dose of cyanide can result in death within minutes
due to the inhibition of cytochrome oxidase resulting in arrest of cellular respiration. Specifically, cyanide binds rapidly with cytochrome a3, a component
of the cytochrome c oxidase complex in mitochondria. Inhibition of cytochrome
a3 prevents the cell from using oxygen and forces anaerobic metabolism, resulting
in lactate production, cellular hypoxia and metabolic acidosis. In massive acute
cyanide poisoning, the mechanism of toxicity may involve other enzyme systems
as well. Signs and symptoms of acute systemic cyanide poisoning may develop
rapidly within minutes, depending on the route and extent of cyanide exposure.

The action of Cyanokit in the treatment of cyanide poisoning is based on its
ability to bind cyanide ions. Each hydroxocobalamin molecule can bind one cyanide
ion by substituting it for the hydroxo ligand linked to the trivalent cobalt
ion, to form cyanocobalamin, which is then excreted in the urine.

Pharmacodynamics

Administration of Cyanokit to cyanide-poisoned patients with the attendant
formation of cyanocobalamin resulted in increases in blood pressure and variable
changes in heart rate upon initiation of hydroxocobalamin infusions.

Pharmacokinetics

Following intravenous administration of hydroxocobalamin significant binding
to plasma proteins and low molecular weight physiological compounds occurs,
forming various cobalamin-(III) complexes by replacing the hydroxo ligand. The
low molecular weight cobalamins-(III) formed, including hydroxocobalamin, are
termed “free cobalamins-(III)”; the sum of free and protein-bound
cobalamins is termed “total cobalamins-(III)”. In order to reflect
the exposure to the sum of all derivatives, pharmacokinetics of cobalamins-(III)
(i.e. cobalamin-(III) entity without specific ligand) were investigated instead
of hydroxocobalamin alone, using the concentration unit μg eq/mL.

Dose-proportional pharmacokinetics were observed following single dose intravenous
administration of 2.5 to 10 g of hydroxocobalamin in healthy volunteers. Mean
free and total cobalamins-(III) Cmax values of 113 and 579 μg eq/mL, respectively,
were determined following a dose of 5 g of hydroxocobalamin. Similarly, mean
free and total cobalamins-(III) Cmax values of 197 and 995 μg eq/mL, respectively,
were determined following the dose of 10 g of hydroxocobalamin. The predominant
mean half-life of free and total cobalamins-(III) was found to be approximately
26 to 31 hours at both the 5 g and 10 g dose level.

The mean total amount of cobalamins-(III) excreted in urine during the collection
period of 72 hours was about 60% of a 5 g dose and about 50% of a 10 g dose
of hydroxocobalamin. Overall, the total urinary excretion was calculated to
be at least 60 to 70% of the administered dose. The majority of the urinary
excretion occurred during the first 24 hours, but red-colored urine was observed
for up to 35 days following the intravenous infusion.

When normalized for body weight, male and female subjects revealed no major
differences in pharmacokinetic parameters of free and total cobalamins-(III)
following the administration of 5 and 10 g of hydroxocobalamin.

Animal Pharmacology

Evidence of the effectiveness of hydroxocobalamin for treatment of cyanide
poisoning was obtained primarily from studies in animals due to the ethical
considerations of performing such controlled studies in humans. While the results
of these animal studies cannot be extrapolated to humans with certainty, the
extrapolation is supported by the understanding of the pathophysiologic mechanisms
of the toxicity of cyanide and the mechanisms of the protective effect of hydroxocobalamin
as examined in dogs. In addition, the results of uncontrolled human studies
and the animal study establish that hydroxocobalamin is likely to produce clinical
benefit in humans.

The effectiveness of hydroxocobalamin was examined in a randomized, placebo-controlled,
blinded study in cyanide-poisoned adult dogs assigned to treatment with vehicle
(0.9% saline), or 75 or 150 mg/kg hydroxocobalamin. Anesthetized dogs were poisoned
by intravenous administration of a lethal dose of potassium cyanide. Dogs then
received vehicle or 75 or 150 mg/kg hydroxocobalamin, administered intravenously
over 7.5 minutes. The 75 and 150 mg/kg doses are approximately equivalent to
5 and 10 g of hydroxocobalamin (respectively) in humans based on both body weight
and the Cmax of hydroxocobalamin (total cobalamins-(III)). Survival at 4 hours
and at 14 days was significantly greater in low-and high-dose groups compared
with dogs receiving vehicle alone (Table 4). Hydroxocobalamin reduced whole
blood cyanide concentrations by approximately 50% by the end of the infusion
compared with vehicle.

Clinical Studies

Smoke Inhalation Victims

A prospective, uncontrolled, open-label study was carried out in 69 subjects
who had been exposed to smoke inhalation from fires. Subjects had to be over
15 years of age, present with soot in the mouth and expectoration (to indicate
significant smoke exposure), and have altered neurological status. The median
hydroxocobalamin dose was 5 g with a range from 4 to 15 g.

Fifty of 69 subjects (73%) survived following treatment with hydroxocobalamin.
Nineteen subjects treated with hydroxocobalamin did not survive. Fifteen patients
treated with hydroxocobalamin were in cardiac arrest initially at the scene;
13 of these subjects died and 2 survived.

Two additional retrospective, uncontrolled studies were carried out in subjects
who had been exposed to cyanide from fire or smoke inhalation. Subjects were
treated with up to 15 g of hydroxocobalamin. Survival in these two studies was
34 of 61 (56%) for one study, and 30 of 72 (42%) for the second.

Cyanide Poisoning by Ingestion or Inhalation

A retrospective, uncontrolled study was carried out in 14 subjects who had
been exposed to cyanide from sources other than from fire or smoke (i.e., ingestion
or inhalation). Subjects were treated with 5 to 20 g of hydroxocobalamin. Eleven
of 12 subjects whose blood cyanide concentration was known had initial blood
cyanide levels considered to be above the lethal threshold.

Ten of 14 subjects (71%) survived, following administration of hydroxocobalamin.
One of the four subjects who died had presented in cardiac arrest. Of the 10
subjects who survived, only 1 subject had neurological sequelae at hospital
discharge. This subject had post-anoxic encephalopathy, with memory impairment,
considered to be due to cyanide poisoning.

Cross-Study Findings

Experience with Dosing Greater than 10 g of Hydroxocobalamin

Across all four uncontrolled studies, 10 patients who did not demonstrate a
full response to 5 or 10 g-doses of hydroxocobalamin were treated with more
than 10 g of hydroxocobalamin. One of these 10 patients survived with unspecified
neurological sequelae.

Effects on Blood Pressure

Initiation of hydroxocobalamin infusion as part of the therapeutic interventions
generally resulted in increases in blood pressure and variable changes in heart
rate (often normalization).

Survival of Patients Presenting in Cardiac Arrest

Of the 245 patients across all four studies, 68 (28%) presented in cardiac
arrest. While blood pressure and heart rate may have been restored in many of
these 68 patients, only five (7%) survived.

Last reviewed on RxList: 5/26/2011
This monograph has been modified to include the generic and brand name in many instances.